1. Field of the Invention
A novel form of artemisinins that are complexed with cyclodextrin for solving stability problems associated with previous forms of artemisinins.
2. Brief Description of Related Art
Artelinic acid is an effective antimalarial agent when in contact with the malarial parasite. However, artelinic acid has poor stability in solution and, thus, has limited bioavailability in vivo. Artemisinins, as a class, include such analogs as artelinic acid and artesunic acid among many others. Currently, no analog of the artemisinin class of compounds exists which can remain stable in solution. Injectable formulations of artemisinin analogs, such as artelinic acid and artesunic acid, are not FDA approved due to their instability in solution. All artemisinins contain a peroxide bridge susceptible to hydrolytic cleavage. Artemisinins have been found to yield an inferior class of antimalarials due to these severe limitations in chemical stability. Artemisinins are limited to only being packaged as solids for oral dosing, as previous patents have claimed. U.S. Pat. Nos. 6,326,023; 6,307,068; 6,306,896; 5,834,491; 5,677,331; 5,637,594; 5,486,535; 5,278,173; 5,270,037; 5,219,865; 5,021,426; 5,011,951.
Application of an antimalarial formulation must be specific to administration in hot, humid tropical regions native to the malarial parasite. Thus, chemical stability under drastic environmental conditions is essential. Attempts to produce a more stable form of artelinic acid have been accompanied by critical limitations. A soluble sodium salt of artelinic acid has been successfully formulated, but eventually degrades over time. This is presumably due to a reformation of the insoluble acid. Numerous attempts at preventing this precipitate have been unsuccessful.
The osmolality of the salt solution is significantly less than the predicted value indicating possible inter-molecular complexation that may be responsible for eventual precipitation over time. An amine-based buffer of artelinic acid has been successfully formulated, but yields a higher pH solution (>8.0) that induces significant vein irritation upon injection. Additional localized redness and swelling surrounding the injection site is a notable contraindication to a preferred intravenous formulation. Additionally, amine-based buffers have been observed to take on a strong yellow hue over time. The mechanism of color formation has not been deduced, but implies a modification of the artelinate formulation, which is not conducive to pharmaceutical preparations where a defined constant state of purity is essential.
U.S. Pat. Nos. 6,326,023; 6,307,068; 6,306,896; 5,834,491; 5,677,331; 5,637,594; 5,486,535; 5,278,173; 5,270,037; 5,219,865; 5,021,426; 5,011,951 are only directed to be packaged as solids for oral dosing.
Therefore, there is a need to provide a form of artemisinins that solve the stability problems associated with previous formulations.
It is an object of the present invention to provide a form of artemisinins, such as but not limited to artelinic acid and artesunic acid that solves the stability problems associated with previous formulations.
It is another object of the present invention to provide a stable form of artemisinins that is injectable.
It is still another object of the present invention to provide a stable form of artemisinins that does not develop a yellow hue over time.
It is still another object of the invention to promote bioavailability and membrane permeability while decreasing the likelihood of localized inflammation at the route of entry, thus increasing its therapeutic activity.
These and other objects of the invention will become apparent upon a reading of the entire disclosure.